ClinGen Dosage Sensitivity Curation Page

USP9X

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26833328 A multi-institutional study identified 17 females with de novo loss-of-function mutations in USP9X and presenting with ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations. Transcript and protein studies confirmed loss of function effect as a result of the mutations.
24607389 Report describes three variants (two missense and one protein truncating) in USP9X in females with syndromic intellectual disability. Loss of Usp9x in mice causes reduction in both axonal growth and neuronal cell migration. In family 1, a missense variant (c.6278T>A, p.Leu2093His) was found in a singleton affected male. In family 2, a second missense variant (c.6469C>A, p.Leu2157Ile) was found in an affected male, his unaffected mother, and his unaffected grandmother. The proband in this second family also had a ?790 kb deletion at 6q25.3, which includes ARID1B. However, parental testing was not performed to determine if it was de novo (as many ARID1B mutations are). In a third family, a single-nucleotide deletion (c.7574delA, p.Gln2525Argfs?18) was identified in two half brothers, their unaffected mother and affected uncle, and their unaffected grandmother. Important to note - the truncating mutation was in the last exon and therefore might escape NMD. The authors showed that overexpression of wild-type human USP9X in. mutant Usp9x mice rescued defects, but all three USP9X variants listed above failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration.
28377321 Report describes two female individuals with ID and various congenital anomalies, reminiscent of UPS9X phenotype (heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, abnormal pigmentation along lines of Blaschko, and Dandy Walker malformation). Phenotype overlaps that of CHARGE syndrome and some ciliopathies such as Joubert and Bardet-Biedl. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion that was associated with a deletion of the 5'UTR of the USP9X. The second individual had a de novo frameshift mutation detected by whole-exome sequencing (c.4104_4105del, p.Arg1368Serfs*2).

Haploinsufficiency phenotype comments:

Other PMID: 24690944 -- A single female individual with a de novo splicing mutation in USP9X was reported. The deleterious effect of the mutation was confirmed by cDNA sequencing. This individual had a constellation of congenital malformations, consistent with USP9X-associated phenotype. General note: The USP9X-related phenotype is largely seen in females, but at least one report describes what appear to be milder mutations in affected males and unaffected female relatives. This needs further corroboration. Severe truncating variants are not present in ExAC and no mutations causing loss of function of USP9X have been reported in males, so it is possible that LOF mutations in this gene are. male-lethal. Absence of Usp9X in male mice is embryonic lethal.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.